This SBIR project is designed to develop a new non-viral carrier for target-specific delivery of small interfering RNA (siRNA). One of the major challenges in transforming siRNA from laboratory reagents to therapeutics is developing a target-specific delivery system to introduce siRNAs into target cells. Maximal therapeutic benefit with decrease in the required drug dose and avoidance of nonspecific silencing and toxicity in nontarget cells could thereby be achieved. This proposal describes a new diblock copolymer with a positively charged block to complex with siRNA, a poly(ethyleneoxide) block for protection against non-specific adsorption, and a phosphane group on the PEG end for targeting ligand conjugation through Staudinger ligation. The Phase II work is expected to investigate the safety and efficacy of this novel siRNA delivery system in an animal model for therapeutic application. Specific aims of this Phase I proposal include: 1) optimize the synthesis of special diblock copolymers; 2) conjugate targeting ligands to diblock copolymers; 3) develop the methodology for preparing siRNA/polymer nanoparticles; 4) evaluate cytotoxicity of the new siRNA delivery system; 5) demonstrate inhibition of gene expression; and 6) investigate intracellular trafficking. [unreadable] [unreadable] [unreadable]